Potential Super Heavy Bomb Stumbles

A potential heavyweight drug stumbled. Yesterday, Sanofi's benchmark respiratory disease pipeline, the OX40L monoclonal antibody Amlitelimab, failed in the Phase II clinical trial for asthma indications. Just last month, Amgen’s similar pipeline, Rocatinlimab, announced its success in the same indication, which boosted confidence in this target. 

Now, Dupixent, with over 14 billion in sales, stands in front of the pipeline, and such a massive single-product market awaits the follow-up drugs to capture. Will the OX40-target monoclonal antibody become a strong competitor? And does this target have other paths to explore? The future expectations of this target, at least in autoimmune inflammation markets, are highly anticipated.

OX40 Target - An Upstream Regulator

The OX40 target is quite similar to PD-1, with two sides of a coin: one side can treat cancer, while the other side can treat autoimmune and inflammatory diseases. This is what makes this target very interesting. Let’s take a look at the mechanism of the OX40 target.

OX40 and its ligand OX40L are important immune system regulatory pathways. As shown in the diagram below, OX40L is expressed on antigen-presenting cells, and OX40 is expressed on activated T cells. When these two connect, immune effects are generated, stimulating the clonal expansion of effector CD4+ and CD8+ T cells, upregulating the expression of pro-inflammatory cytokines, and promoting T cell survival.

As we previously discussed, the dual nature of the immune system: when it is too strong, it leads to inflammation and autoimmune diseases; when it is too weak, it leads to cancer. For the OX40-OX40L combination, there are several pathways that must be mentioned.

• PI3K-PKB/Akt pathway and NF-κB1 pathway. The PI3K-PKB/Akt pathway has a very positive effect on cell growth and metabolism, while the NF-κB1 pathway stimulates the production of anti-apoptotic proteins within cells, promoting T cell survival. These two are fundamental principles. When the OX40-OX40L target is activated, it promotes the activation of both the PI3K-PKB/Akt pathway and the NF-κB1 pathway, thereby promoting T cell growth and anti-apoptosis.
• FoxP3 expression. The expression of FoxP3 in CD+ T cells promotes the production of Treg cells, which are regulatory T cells that have a negative impact on the immune system. When the OX40 pathway is activated, FoxP3 expression within T cells is downregulated, inhibiting the production of Tregs and reducing immune suppression.
• Inflammatory microenvironment. In the inflammatory microenvironment, inflammatory cytokines such as IL-4 and IFN-γ are enriched. When these factors are present and the OX40 pathway is activated, it leads to the preferential expansion of effector CD4+ T cells, promoting immune responses.

This is the general mechanism of OX40 in inflammation and autoimmune diseases. It indirectly regulates cytokines by modulating T cells. This indirect effect has both advantages and disadvantages, which will be seen in clinical practice later.

From this perspective, since activating the OX40-OX40L pathway enhances immune responses, the approach is to find ways to inhibit this activation. Hence, monoclonal antibodies targeting this pathway have been developed. Currently, there are two leading monoclonal antibodies targeting OX40: Amgen's Rocatinlimab and Sanofi's Amlitelimab.

The Long Journey of OX40 Monoclonal Antibodies

Looking at the current landscape of autoimmune drugs, the top three single drugs are Sanofi/Regeneron's Dupixent, which targets IL-4R, and quickly became a blockbuster upon its release. Next is Abbvie's Risankizumab, targeting IL-23, which was approved in 2019 and also quickly became a blockbuster. Then there is Johnson & Johnson's Ustekinumab, which has been on the market for a long time (FDA approved in 2009) and targets the IL-12 and IL-23 p40 subunits. Additionally, there is Novartis' Secukinumab, targeting IL-17, which was approved in 2017.

The problem now is that autoimmune targets seem to have entered a state of homogenization, as seen from the number of IL-17 and IL-23 monoclonal antibodies approved in China over the past few years. What is the way out? On one hand, some companies are pursuing a combination approach with existing targets to create dual antibodies, which is a safer route. Major pharmaceutical companies like Innovent, Kangle, and Heng Rui are working on this, which has a lower risk and is not difficult to achieve therapeutic effects. However, whether this is an urgent iteration is a question. On the other hand, companies are looking for new targets. This route is riskier, but someone needs to take on the challenge of creating something from scratch.

The OX40 target is one such new target being explored. From cancer activators to autoimmune/inflammation inhibitors, it is a novel target with multiple clinical pipelines. The earliest clinical pipeline for autoimmune diseases is KHK4083, developed by Chugai Pharmaceutical. Clinical trials started in 2016 for ulcerative colitis, but the pipeline became well-known for its use in atopic dermatitis. In February 2021, Chugai’s KHK4083 showed excellent clinical results in Phase II trials for atopic dermatitis, and by June, a deal was struck with Amgen to co-develop the drug, with an upfront payment of $400 million and milestone payments of up to $850 million. Now, it is called Rocatinlimab or AMG-451.

The success of the atopic dermatitis indication in Phase II and III trials has now positioned it to become the first OX40 monoclonal antibody to be marketed globally. Let’s analyze the Phase III clinical data. The three Phase III clinical trials are the ROCKET-IGNITE, ROCKET-SHUTTLE, and ROCKET-HORIZON studies.

Using the HORIZON study as an example, 726 patients were randomly assigned in a 3:1 ratio to receive Rocatinlimab or a placebo, with subcutaneous injections every 4 weeks after a loading dose. The Rocatinlimab dose was 300 mg. The primary combined endpoint was the Investigator Global Assessment (vIGA-AD) score of 0 or 1 (clear or almost clear) and a 75% or greater reduction in the Eczema Area and Severity Index (EASI-75).

The results showed that the EASI-75 response rate for the Rocatinlimab group was 32.8%, compared to 13.7% for the placebo group. The vIGA-AD 0/1 response rate was 19.3% for Rocatinlimab and 6.6% for placebo. However, the Phase III trial was interpreted as slightly below expectations because in Phase II, the 300mg dose group had a vIGA-AD 0/1 response rate of 30.8%. But compared to the placebo, the efficacy is still very good. A decrease in efficacy from Phase II to III is common. However, it may face the problem of efficacy being lower than Dupixent’s. In non-head-to-head trials, Dupixent’s Phase III response rate is about 36%-38%, with an EASI-75 response rate around 50%.

From a mechanistic standpoint, the efficacy can be explained by the OX40 monoclonal antibody's action being upstream and indirect, requiring internal T cell signaling to take effect, unlike IL-17's direct action. This highlights the rarity of highly effective direct-acting targets like IL-17.

Just like the GLP-1 target for weight loss medications is hard to come by, many highly effective targets are discovered through trial and error. Other targets for the same indication may have some efficacy but not as striking. Some effects are noticeable in Phase I, while others may only be apparent in the final Phase III trials.

Of course, OX40 as an upstream target has its advantages. As discussed in "A Rising Heavy Bomb," downstream monoclonal antibodies cannot address the itch-scratch-itch problem effectively, but OX40 monoclonal antibodies, as upstream inhibitors, can better regulate the Th1/Th2/Th17/Th22 pathways and somewhat address the itching in atopic dermatitis. This will improve patient compliance and serve as a differentiation advantage for OX40.

Prospects of Amlitelimab

Amlitelimab is also part of Sanofi's high-value BD pipeline. It was originally developed by Kymab, a biotech company acquired by Sanofi in January 2021 for an upfront payment of $1.1 billion and milestone payments of $350 million. The main reason for the acquisition was to obtain the global rights to KY1005, which later became Amlitelimab. Sanofi has high expectations for it, with a peak sales forecast of €5 billion. To achieve this figure, multiple indications must support the drug. The indications for Amlitelimab are shown in the diagram below:

Asthma is just one of many indications. In fact, Amlitelimab has relatively good clinical data for atopic dermatitis. At the highest dose, the IGA 0/1 response rate at 24 weeks reached 45.5%, and the EASI-75 response rate reached 54.5%, which is impressive. However, the old problem remains: can this efficacy be sustained in Phase III trials? It is still too early to make a definitive statement that Amlitelimab will be "best in class." Phase III data is expected to be available next year.

Regarding asthma, while its failure may result in some loss of market share, as shown in the indication layout above, this does not necessarily mean a death sentence for the drug. The main opportunity remains in the atopic dermatitis market.

Apart from Amgen and Sanofi's OX40 monoclonal antibodies, Chuangxiang Biotech (now merged with IKNA) has one of the most impressive OX40 antibodies. A few months ago, it released the topline results of its Phase IIa clinical trial. This monoclonal antibody is now under the management of InnoCare Pharma.

The Fc segment of this antibody silences ADCC function, improving the drug’s tolerability, such as avoiding fever or chills. Its main advantage is the ultra-long dosing interval, allowing for administration once every six months. For specific Phase IIa clinical trial data, refer to "Another Biotech Succeeds."

What we might deeply reflect on from this discussion is the question: how will autoimmune disease targets develop in the future? If we draw a parallel to cancer, the trend in cancer antibodies in recent years has been to combine therapies, from monoclonal antibodies to bispecific and trispecific antibodies. This is the most stable route. Even if bispecific antibodies may not offer a significant differentiation advantage over monoclonal antibodies, at least they are effective. On the other hand, exploring new targets comes with the risk of efficacy being no better than placebo, leading to years of effort and huge investment going to waste. This high-risk undertaking is something that US biotech companies are willing to attempt, but Chinese biotech companies may not be able to afford.

From cancer to autoimmune diseases, the reasoning may be similar. That’s why large pharmaceutical companies such as Innovent and Kangle are developing bispecific antibodies in autoimmune diseases, hoping that the additive effect will produce better efficacy. This stable pipeline development strategy is understandable.

Conclusion

The key insight we can gain from OX40 is that new targets may be effective, but they are not necessarily superior to older targets. Some old targets are revolutionary and irreplaceable. However, in an era of economic prosperity and easy financing, such exploration still holds significant value. But in a harsh winter where refinancing is difficult, the uncertainty of new targets may make them seem challenging and untimely.